TY - JOUR
T1 - Building native protein conformation from highly approximate backbone torsion angles
AU - Gong, Haipeng
AU - Fleming, Patrick J.
AU - Rose, George D.
PY - 2005/11/8
Y1 - 2005/11/8
N2 - Reconstructing a protein in three dimensions from its backbone torsion angles is an ongoing challenge because minor inaccuracies in these angles produce major errors in the structure. As a familiar example, a small change in an elbow angle causes a large displacement at the end of your arm, the longer the arm, the larger the displacement. Even accurate knowledge of the backbone torsions φ and ψ is insufficient, owing to the small, but cumulative, deviations from ideality in backbone planarity, which, if ignored, also lead to major errors in the structure. Against this background, we conducted a computational experiment to assess whether protein conformation can be determined from highly approximate backbone torsion angles, the kind of information that is now obtained readily from NMR. Specifically, backbone torsion angles were taken from proteins of known structure and mapped into 60° × 60° grid squares, called mesostates. Side-chain atoms beyond the β-carbon were discarded. A mesostate representation of the protein backbone was then used to extract likely candidates from a fragment library of mesostate pentamers, followed by Monte Carlo-based fragment-assembly simulations to identify stable conformations compatible with the given mesostate sequence. Only three simple energy terms were used to gauge stability: molecular compaction, soft-sphere repulsion, and hydrogen bonding. For the six representative proteins described here, stable conformers can be partitioned into a remarkably small number of topologically distinct clusters. Among these, the native topology is found with high frequency and can be identified as the cluster with the most favorable energy.
AB - Reconstructing a protein in three dimensions from its backbone torsion angles is an ongoing challenge because minor inaccuracies in these angles produce major errors in the structure. As a familiar example, a small change in an elbow angle causes a large displacement at the end of your arm, the longer the arm, the larger the displacement. Even accurate knowledge of the backbone torsions φ and ψ is insufficient, owing to the small, but cumulative, deviations from ideality in backbone planarity, which, if ignored, also lead to major errors in the structure. Against this background, we conducted a computational experiment to assess whether protein conformation can be determined from highly approximate backbone torsion angles, the kind of information that is now obtained readily from NMR. Specifically, backbone torsion angles were taken from proteins of known structure and mapped into 60° × 60° grid squares, called mesostates. Side-chain atoms beyond the β-carbon were discarded. A mesostate representation of the protein backbone was then used to extract likely candidates from a fragment library of mesostate pentamers, followed by Monte Carlo-based fragment-assembly simulations to identify stable conformations compatible with the given mesostate sequence. Only three simple energy terms were used to gauge stability: molecular compaction, soft-sphere repulsion, and hydrogen bonding. For the six representative proteins described here, stable conformers can be partitioned into a remarkably small number of topologically distinct clusters. Among these, the native topology is found with high frequency and can be identified as the cluster with the most favorable energy.
KW - Monte Carlo simulation
KW - Protein fragment assembly
KW - Protein secondary structure
KW - Protein structure
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U2 - 10.1073/pnas.0508415102
DO - 10.1073/pnas.0508415102
M3 - Article
C2 - 16251268
AN - SCOPUS:28044472257
SN - 0027-8424
VL - 102
SP - 16227
EP - 16232
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -